Substituted heterocyclic compounds

ABSTRACT

Disclosed are novel substituted heterocyclic derivatives having the structure of Formula I: 
                         
The compounds are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal&#39;s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, diabetes, and myocardial infarction.

This application is a Divisional application of U.S. patent applicationSer. No. 11/452,479, filed Jun. 13, 2006, now issued as U.S. Pat. No.7,262,198, which was a Divisional application of U.S. patent applicationSer. No. 11/015,915, filed Dec. 17, 2004, now issued as U.S. Pat. No.7,115,610, which claimed priority to U.S. Provisional Patent ApplicationSer. No. 60/531,253, filed Dec. 18, 2003, all of which are incorporatedby reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds and totheir use in the treatment of various disease states, includingcardiovascular diseases such as atrial and ventricular arrhythmias,intermittent claudication, Prinzmetal's (variant) angina, stable andunstable angina, exercise induced angina, congestive heart disease,ischemia, reperfusion injury and myocardial infarction, and diabetes anddisease states related to diabetes. The invention also relates tomethods for their preparation, and to pharmaceutical compositionscontaining such compounds.

BACKGROUND OF THE INVENTION

Certain classes of piperazine compounds are known to be useful for thetreatment of cardiovascular diseases, including arrhythmias, angina,myocardial infarction, and related diseases such as intermittentclaudication. For example, U.S. Pat. No. 4,567,264 discloses a class ofsubstituted piperazine compounds that includes a compound known asranolazine,(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,and its pharmaceutically acceptable salts, and their use in the abovedisease states.

Despite the desirable properties demonstrated by ranolazine, which is avery effective cardiac therapeutic agent, believed to function as afatty acid oxidation inhibitor and late sodium channel blocker, thereremains a need for compounds that have similar therapeutic properties toranolazine, but are more potent and have a longer half-life.

SUMMARY OF THE INVENTION

It is an object of this invention to provide novel substitutedheterocyclic compounds that function as fatty acid oxidation inhibitorsand/or late sodium channel blockers. Accordingly, in a first aspect, theinvention relates to compounds of Formula I:

wherein:

-   -   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, lower alkyl, or        —C(O)R, in which R is —OR¹¹ or —NR¹¹R¹², where R¹¹ and R¹² are        hydrogen or lower alkyl; or    -   R¹ and R², R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, when taken together        with the carbon to which they are attached, represent carbonyl;        or    -   R¹ and R⁵, or R¹ and R⁷, or R³ and R⁵, or R³ and R⁷, when taken        together form a bridging group —(CR¹²R¹³)_(n)—, in which n is 1,        2 or 3, and R¹² and R¹³ are independently hydrogen or lower        alkyl;        -   with the proviso that            -   the maximum number of carbonyl groups is 1;            -   the maximum number of —C(O)NR¹¹R¹² groups is 1; and            -   the maximum number of bridging groups is 1;    -   R⁹ and R¹⁰ are independently optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted cycloalkyl, optionally substituted        heterocycle, optionally substituted aryl, or optionally        substituted heteroaryl;    -   T is —O—, —S—, —NHSO₂—, —SO₂NH—, or —CO—NH—; or    -   R⁹ and T when taken together are optionally substituted        heterocyclyl;    -   Q is —N< or —NH—CH<;    -   X is a covalent bond or an optionally substituted alkylene of        1-6 carbon atoms;    -   Y is optionally substituted alkylene of 1-3 carbon atoms; and    -   Z is a covalent bond, —O—, —S—, or —N(R¹⁵)—, wherein R¹⁵ is        hydrogen or C₁₋₄ alkyl.

A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I and at least one pharmaceutically acceptableexcipient.

A third aspect of this invention relates to a method of using thecompounds of Formula I in the treatment of a disease or condition in amammal that is amenable to treatment by a fatty acid oxidation inhibitoror late sodium channel blocker. Such diseases include, but are notlimited to, protection of skeletal muscles against damage resulting fromtrauma, intermittent claudication, shock, and cardiovascular diseasesincluding atrial and ventricular arrhythmias, Prinzmetal's (variant)angina, stable angina, exercise induced angina, congestive heartdisease, diabetes, and myocardial infarction. The compounds of Formula Iare also useful for lowering plasma level of HbAlc, lowering glucoseplasma levels, lowering total cholesterol plasma levels, loweringtriglyceride plasma levels, raising HDL cholesterol levels, and/ordelaying onset of diabetic retinopathy. They can also be used topreserve donor tissue and organs used in transplants.

The preferred compounds presently include:

-   (2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-methylphenyl)sulfonyl]amine;-   N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzamide;-   (4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide;-   (4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]propan-2-ol;-   (2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   (3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-chlorophenyl)pyrrolidin-2-one;-   (3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(2-fluorophenyl)pyrrolidin-2-one;-   (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol;-   (2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl}propan-2-ol;-   (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-    methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperaziny}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(phenylsulfonyl)amine;-   [2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine;-   3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-chlorophenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-trifluoromethoxy)phenylsulfonyl]amine;-   (3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,5-dimethyl)phenylsulfonyl]amine;-   {[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(methyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine;-   [3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   (4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]naphthylamine;-   [(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl)sulfonyl][4-(tertbutyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine;-   (2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   [(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(3-methylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(naphthylsulfonyl)amine;-   {[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   [(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   {[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl    }ethyl)amine;-   (3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine;-   1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-phenylazolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-naphthylazolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-    yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-naphthylazolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-methylphenyl)azolidine-2,5-dione;-   1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylpyrrolidin-2-one;-   1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   (2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol;-   6-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)-2,3a,7a-trihydrobenzo[2,    1-b]furan-3-one;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]acetate;-   ethyl    3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoate;-   2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]acetic    acid;-   (2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-methylphenyl)pyrrolidin-2-one;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-vinylphenyl)azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylazolidine-2,5-dione;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetate;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoate;-   2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoic    acid;-   3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoic    acid;-   (2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol;-   (2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetic    acid;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy]hexyl}piperazinyl)propan-2-ol;-   (2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohexyloxy]butyl}piperazinyl)propan-2-ol;-   (3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}pyrrolidin-2-one;-   4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one;    and-   4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one.    Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, preferably 1 to 3 substituents, selected from the        group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl,        cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,        —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and        —SO₂-heteroaryl. Unless otherwise constrained by the definition,        all substituents may optionally be further substituted by 1, 2,        or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, or        heteroaryl and n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms independently chosen from oxygen, sulfur and NR_(a)—,        where R_(a) is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,        cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All        substituents may be optionally further substituted by alkyl,        alkoxy, halogen, CF₃, amino, substituted amino, cyano, or        —S(O)_(n)R, in which R is alkyl, aryl, or heteroaryl and n is 0,        1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6carbon atoms. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents, preferably 1, 2, or 3 substituents, asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substitutedalkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1, 2, 3,4, or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 20 carbonatoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6carbon atoms. This term is exemplified by groups such as methylene(—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—) and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

The term “substituted alkylene” refers to:

-   -   (1) an alkylene group as defined above having 1, 2, 3, 4, or 5        substituents selected from the group consisting of alkyl,        alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,        acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,        azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,        carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,        alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,        aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,        hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,        —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless        otherwise constrained by the definition, all substituents may        optionally be further substituted by 1, 2, or 3 substituents        chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,        hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,        and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is        0, 1 or 2; or    -   (2) an alkylene group as defined above that is interrupted by        1-20atoms independently chosen from oxygen, sulfur and NR_(a)—,        where R_(a) is chosen from hydrogen, optionally substituted        alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and        heterocyclyl, or groups selected from carbonyl, carboxyester,        carboxyamide and sulfonyl; or    -   (3) an alkylene group as defined above that has both 1, 2, 3, 4        or 5 substituents as defined above and is also interrupted by        1-20 atoms as defined above. Examples of substituted alkylenes        are chloromethylene (—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—),        methylaminoethylene (—CH(NHMe)CH₂—), 2-carboxypropylene        isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),        ethylmethylaminoethyl (—CH₂CH₂N(CH₃)CH₂CH₂—),        1-ethoxy-2-(2-ethoxy-ethoxy)ethane        (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-O—and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl as defined above. This term isexemplified by groups such as methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 20 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl).Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂), 1-propyleneor allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon. preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or propynyl, —C≡CCH₃), and the like. In the eventthat alkynyl is attached to nitrogen, the triple bond cannot be alpha tothe nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano, or —S(O)_(n)R_(a), in which R_(a) is alkyl,aryl, or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl,—O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “aryl” refers to an aromatic carboxyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl, and anthryl). Preferred aryls include phenyl, fluorenyl,naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents, preferably 1, 2, or 3 substituents, selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1, 2, or 3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen, or a group —Y-Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbons atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic group (i.e., unsaturated)comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen, and sulfur within at least one ring.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1, 2, or 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl (an alkyl ester), arylthio, heteroaryl,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazole, orbenzothienyl). Examples of nitrogen heterocycles and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated group having asingle ring or multiple condensed rings, having from 1 to 40 carbonatoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms,selected from nitrogen, sulfur, phosphorus, and/or oxygen within thering.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1, 2, or 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Heterocyclic groups can have a single ring or multiple condensed rings.Preferred heterocyclics include tetrahydrofuranyl, morpholino,piperidinyl, and the like.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfone” refers to a group —S(O)₂R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” refersto a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, hydrates, polymorphs, andprodrugs of such compounds. Additionally, the compounds of the inventionmay possess one or more asymmetric centers, and can be produced as aracemic mixture or as individual enantiomers or diastereoisomers. Thenumber of stereoisomers present in any given compound of Formula Idepends upon the number of asymmetric centers present (there are 2^(n)stereoisomers possible where n is the number of asymmetric centers). Theindividual stereoisomers may be obtained by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis, or by resolution of the compound of Formula I by conventionalmeans. The individual stereoisomers (including individual enantiomersand diastereoisomers) as well as racemic and non-racemic mixtures ofstereoisomers are encompassed within the scope of the present invention,all of which are intended to be depicted by the structures of thisspecification unless otherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R—S system. When the compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, polymorphs, and prodrugs ofsuch compounds.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds of FormulaI, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases, includeby way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Fatty acid oxidation inhibitors” refers to compounds that suppress ATPproduction from the oxidation of fatty acids and consequently stimulateATP production from the oxidation of glucose and lactate. In the heart,most of the ATP production is acquired through the metabolism of fattyacids. The metabolism of glucose and lactate provides a lesserproportion of ATP. However, the generation of ATP from fatty acids isless efficient with respect to oxygen consumption than the generation ofATP from the oxidation of glucose and lactate. Thus, the use of fattyacid oxidation inhibitors results in more energy production per moleculeof oxygen consumed, allowing the heart to be energized more efficiently.Fatty acid oxidation inhibitors are especially useful, therefore, fortreating an ischemic environment in which oxygen levels are reduced.

Nomenclature

The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which whereR⁹ is 4-chromanyl, R¹⁰ is 2-methylbenzothiazol-5-yl, T is —O—, X is—(CH₂)₄—, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen, Y ismethylene, and Z is oxygen;

which is named: (2R)-1-[4-(4-chroman-4-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-olSynthetic Reaction Parameters

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith [including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like]. Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula I

The compounds of the invention may be prepared using conventional andwell-known synthetic methods. Typically, the portion of the moleculecontaining the central nitrogen heterocycle is prepared first and thenthe desired Y-Z-R⁹ substituents added. When T is O, S, or —CO—NH—, orwhen R⁹ and T form an optionally substituted heterocyclic ring, theaddition of the X-T-R⁹ substituents may be accomplished using a simplesubstitution reaction. Reaction Scheme I illustrates this generalsynthetic pathway when Q is —N<.

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X, Y, and Z are asdefined in the Summary of the Invention, Hal is halogen, and t-but istertiary butyl.

Starting Materials

The compounds of formula (1), (2), and (4) are either commerciallyavailable or can be made by conventional methods well known to those ofordinary skill in the art.

For example, the precursor to a compound of formula (4) where R¹ and R⁵when taken together represent a bridging methylene group, i.e.;

is commercially available [(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane],or can be made by a procedure disclosed in J. Org. Chem., 1990, 55,1684-7. Similarly, the precurso to a compound of formula (4) where R¹and R⁵ when taken together represent a bridging methylene group, and theprecursor to a compound of formula (4) where R¹ and R⁷ when takentogether represent a bridging methylene group, can be made by publishedprocedures found in J. Med. Chem., 1974, 17, 481-7. The precursor to acompound of formula (4) in which R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ arehydrogen and R⁸ is —C(O)NH₂ is prepared from piperazine-2-carboxamide, acommercially available compound.

Step 1—Preparation of Formula (3)

The compound of formula (3) is prepared conventionally by reaction of acompound of formula (1), for example 5-hydroxy-2-methylbenzothiazole,with an epoxide of formula (2), which may be racemic or chiral. Ingeneral, the two compounds are mixed in an inert solvent, preferably aketone, for example acetone, and a tertiary organic base or an inorganicbase, preferably potassium carbonate, at a temperature of about reflux,for about 8-48 hours, preferably overnight. When the reaction issubstantially complete, the product of formula (3) is isolated byconventional means, for example by filtration, removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel. Alternatively, the product can be crystallized from thefiltrate after filtration.

Step 2—Preparation of Formula (5)

The compound of formula (3) is then reacted with a protected piperazineof formula (4). In general, the two compounds are mixed in an inertsolvent, preferably a halogenated solvent, for example methylenechloride, optionally in the presence of a catalyst, for exampleytterbium (III) trifluoromethanesulfonate. In the presence of a catalystthe reaction is conducted at about 0-30° C., preferably at about roomtemperature, for about 8-48 hours, preferably overnight. In the absenceof a catalyst, the mixture is refluxed for a similar period of time inethanol in the presence of triethylamine. When the reaction issubstantially complete, the product of formula (5) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

Step 3—Preparation of Formula (6)

The compound of formula (5) is then deprotected by hydrolyzing the N-Bocprotected carbamate. In general, the compound of formula (5) isdissolved in a mixture of an inert solvent, preferably a halogenatedsolvent, for example methylene chloride, and a strong acid, for exampletrifluoroacetic acid. The reaction is conducted at about 0-30° C.,preferably at about room temperature, for about 8-48 hours, preferablyovernight. When the reaction is substantially complete, the product offormula (6) is isolated by conventional means, for example by adding abase to remove excess acid, and removal of the solvent under reducedpressure.

Step 4—Preparation of a Compound of Formula I

The compound of formula (6) is then reacted with a compound of formula(7) (R⁹-T-X-Hal), for example (4-bromobutoxy)cyclopentane. Examples ofsuch compounds are 3(4-chlorobutoxy) benzene,2-bromo-1-(2-methylphenoxy) ethane, or 4-bromo-1-indan-5-yloxybutane,and the like. Such compounds are either commercially available, preparedby means well known in the art (see, for example, see J. Med. Chem,1996, 39, 237-243) or prepared as shown herein. In general, the twocompounds are mixed in an inert solvent, preferably a protic solvent,for example ethanol, in the presence of an inorganic or tertiary organicbase, preferably triethylamine. The reaction is conducted at about30-100° C., preferably at about reflux, for about 8-48 hours, preferablyovernight. When the reaction is substantially complete, the product ofFormula I is isolated by conventional means, for example by removal ofthe solvent under reduced pressure, followed by chromatography.

Variations to the Synthesis of the Compounds of Formula I

Alternative Preparation of Formula (6)

A modified procedure can be used for preparing compounds of formula (6)in which R⁸ is lower alkyl and R¹-R⁷ are hydrogen that avoids the use ofa protecting group. An example where R⁸ is methyl is shown in ReactionScheme IA.

The compound of formula (3) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in a protic solvent, for exampleethanol. The reaction is conducted at about 5-100° C., preferably atabout 80° C., for about 1-12 hours, preferably about 5 hours. When thereaction is substantially complete, the product of formula (6) isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel.

The compound of formula (6) is then reacted with a compound of formula(7) as described above in Reaction Scheme I, step 4, to provide acompound of Formula I in which R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ arehydrogen and R⁸ is methyl.

Alternative Preparations Using a Compound of Formula (7a)

Alternatively, the R⁹-T-X moiety may be added to the central ring priorto addition of the CH₂—CH(OH)—Y-Z-R¹⁰ substituent. An example where andR¹-R³ and R⁵-R⁸ are hydrogen and R⁴ is methyl is shown in ReactionScheme IB.

The compound of formula (7) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in an inert solvent, preferably aprotic solvent, for example ethanol, in the presence of an inorganic ortertiary organic base, preferably triethylamine. The reaction isconducted at about 30-100° C., preferably at about 80° C., for about2-12 hours, preferably about 8 hours. When the reaction is substantiallycomplete, the product of formula (7a) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography.

The compound of formula (7a) is then reacted with an epoxide of formula(3) as described in Reaction Scheme I, step 2, to provide a compound ofFormula I in which R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ are hydrogen and R⁴ ismethyl.

The compound of formula (7a) may also be synthesized by using a vinylderivative of the compound of formula (7). An example where and R¹-R³and R⁵-R⁸ are hydrogen and R⁴ is methyl is shown in Reaction Scheme IC.

The compound of formula (7′) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in an inert solvent, preferably aprotic solvent, for example acetic acid. The reaction is conducted atabout 30-100° C., preferably at about 50° C., for about 8-24 hours,preferably about 14 hours. When the reaction is substantially complete,the product of formula (7a) is isolated by conventional means, forexample by removal of the solvent under reduced pressure, followed bychromatography.

Compounds of formula (7′) may also be reacted with compounds having thestructure of formula (6) to provide Formula I compounds. As describedabove, the two compounds will be mixed in an inert, protic solvent, suchas acetic acid and allowed to react at 30°-100° C. for approximately 8to 24 hours. The Formula I compound may then be isolated and purifiedusing conventional methods.

It will be appreciated that a protected version of the central ring mayalso be used in the synthesis of the compound of formula (7a). Anexample where and R¹-R³ and R⁵-R⁸ are hydrogen and R⁴ is methyl is shownin Reaction Scheme ID.

The compound of formula (7) is reacted with N-Boc protected2-methylpiperazine according to the procedure described for step 2. Theresulting protected compound, here (7a′), is then deprotected as done instep 3 to produce the compound of formula (7a).

Alternative Preparations for Compounds wherein Q is —NH—CH<

Methods Using a Compound of Formula (4a)

A method similar to the method depicted in Reaction Scheme I may beemployed to prepare compounds of Formula I in which Q is —NH—CH<,starting from a compound of formula (4a):

Compounds of formula (4a), which are optionally substituted4-aminopiperidines, protected as BOC derivatives, are eithercommercially available, or can be made by means well known in the art.The compound of formula (4a) is then reacted as shown in steps 2, 3, and4 above, to provide a compound of Formula I in which X is —NH—CH.

Methods Using a Compound of Formula (4b)

An additional method that may be employed to prepare compounds ofFormula I in which Q is —NH—CH<, starts from a compound of formula (4b):

Compounds of formula (4b), which are optionally substitutedpiperidin-4-ones, usually obtained in the form of an HCl salt, areeither commercially available, or can be made by means well known in theart. The compound of formula (4b) is reacted with a compound of formula(3)as shown in step 2 above to provide a compound of formula (5b):

The compound of formula (5b) is then reacted with an amine derivative ofa compound of formula (7), i.e., a compound of formula (7b)(R⁹-T-X—NH₂), for example(3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one,(3R)-3-amino-1-(4-fluorophenyl)pyrrolidin-2-one,(3R)-3-amino-1-(4-methylphenyl)pyrrolidin-2-one, or(3R)-3-amino-1-(2-chloro-4-fluoro-phenyl)pyrrolidin-2-one, and the like.Such compounds are either commercially available, prepared by means wellknown in the art (see, for example, see J. Med. Chem, 1996, 39, 237-243)or prepared as shown herein.

In general, the two compounds are mixed in an inert solvent, preferablya protic solvent, for example ethanol, in the presence of an inorganicor tertiary organic base and/or other reducing agent. One preferredcombination of base/reducing agent is a mixture of diisopropylamine andsodium triacetoxyborohydride. The reaction is conducted at about 20-30°C., preferably at room temperature, for about 8-72 hours, preferably forat least two days. When the reaction is substantially complete, theproduct of Formula I is isolated by conventional means, for example byremoval of the solvent under reduced pressure, followed bychromatography.

Alternative Preparations for Compounds wherein T is —SO₂—NH— or —NH—SO₂—

Methods when T is —SO₂—NH—

When T is —SO₂—NH— or —NH—SO₂—, the synthesis will generally be moreinvolved. In instances when T is —SO₂—NH—, the T moiety will be formedin place with the innermost amino first bound to the core of themolecule and then the sulfonyl portion added in a final step. A suitablereaction pathway is depicted in Reaction Scheme II. It will be noted bythose of ordinary skill in the art that, in Reaction Scheme II, X cannotbe a covalent bond.

Step 1—Preparation of Formula (9)

As shown in Reaction Scheme II, a haloalkylphthalimide is reacted atapproximately 80° C. to approximately 100° C. with a compound of formula(6) in triethylamine for 12 to 24 hours. It should be noted that acompound of formula (6a) could also be used. The resulting product, acompound of formula (9), may be concentrated and purified usingconventional method.

Step 2—Preparation of Formula (10)

The compound of formula (9) is placed in a polar solvent such asmethanol and reacted with hydrazine hydrate for 12 to 18 hours. Acid,such as HCl, is added to the solution and the mixture is heated toapproximately 85° C. for one hour. The application of heat and additionof acid results in the precipitation of phthalimide residue fromsolution. The compound of formula (10) is then purified from thefiltrate by first raising the pH of the filtrate to approximately 14 andthen extracting the compound with a solvent such as Et₂O.

Step 3—Preparation of Formula (11), a Compound of Formula I

Once the amine compound of formula (10) has been prepared, the R⁹—SO₂portion of the Formula I compound is added by simple substitution. Ahalogenated sulfonyl compound, such as a sulfonyl chloride, may be usedand is typically reacted in a polar solvent such as dimethoxyethane for1 to 20 hours at 0° C. The resulting Formula I compound, here a compoundof formula (11), may then be purified using conventional methods.

Methods when T is —NH—SO₂—

In instances when T is —NH—SO₂—, a halogen-based substitution reactionmay be used to synthesize the desired compound. The halogenatedprecursor may be obtained commercially or may be conventionallysynthesized. A suitable reaction pathway is depicted in Reaction SchemeIII.

Step 1—Preparation of Formula (13)

As shown in Reaction Scheme III, an R⁹-amine precursor (11) is reactedwith a dihaloalkylsulfonyl compound of formula (12) in triethylamine andthen rinsed with acid. Conventional separation and purification providesthe resulting vinyl substituted R⁹ sulfonamide precursor of formula(13).

Step 2—Preparation of a Compound of Formula I

Once the vinyl substituted R⁹ sulfonamide precursor of formula (13) hasbeen prepared, it may be reacted with compound of formula (6), oroptionally (6a), to provide the desired Formula I compound. Generally,this reaction takes place in a polar solvent such as EtOH in thepresence of diisopropylethylamine (DIEA). The resulting Formula Icompound, here a compound of formula (14), may then be purified usingconventional methods.

As before, a different procedure may be used were the R⁹-T-X moiety maybe added to the central ring prior to addition of the CH₂—CH(OH)—Y-Z-R¹⁰substituent. An example where R¹-R³ and R⁵-R⁸ are hydrogen, R⁴ ismethyl, and X is ethylene is shown in Reaction Scheme IIIA.

The compound of formula (13) is reacted with 2-methylpiperazine. Ingeneral, the two compounds are mixed in an inert solvent, preferably aprotic solvent, for example ethanol, in the presence of an inorganic ortertiary organic base, preferably triethylamine. The reaction isconducted at about 30-100° C., preferably at about 80° C., for about2-12 hours, preferably about 8 hours. When the reaction is substantiallycomplete, the product of formula (7b) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography.

The compound of formula (7b) is then reacted with an epoxide of formula(3) as described in Reaction Scheme I, step 2, to provide a compound ofFormula I in which R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ are hydrogen, R⁴ ismethyl, and T is —NH—SO₂—.

Utility, Testing and Administration

General Utility

The compounds of Formula I are effective in the treatment of conditionsknown to respond to administration of fatty acid oxidation inhibitorsand/or late sodium channel blockers, including protection of skeletalmuscles against damage resulting from trauma, intermittent claudication,shock, and cardiovascular diseases including atrial and ventriculararrhythmias, Prinzmetal's (variant) angina, stable angina, unstableangina, ischemia and reperfusion injury in cardiac, kidney, liver andthe brain, exercise induced angina, congestive heart disease, andmyocardial infarction. The compounds of Formula I can also be used topreserve donor tissue and organs used in transplants, and may beco-administered with thrombolytics, anticoagulants, and other agents.

Testing

Activity testing is conducted as described in those patents and patentapplications referenced above, and in the Examples below, and by methodsapparent to one skilled in the art.

Pharmaceutical Compositions

The compounds of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

Administration

The compounds of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parental, particularly by injection. Theforms in which the novel compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof Formula I in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Compounds of Formula I may be impregnated into a stent by diffusion, forexample, or coated onto the stent such as in a gel form, for example,using procedures known to one of skill in the art in light of thepresent disclosure.

Oral administration is another route for administration of the compoundsof Formula I. Administration may be via capsule or enteric coatedtablets, or the like. In making the pharmaceutical compositions thatinclude at least one compound of Formula I, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be in the form of asolid, semi-solid, or liquid material (as above), which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds of Formula I are effective over a wide dosage range and aregenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 1 mgto 2 g of a compound of Formula I, and for parenteral administration,preferably from 0.1 to 700 mg of a compound of Formula I. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Preparation of a Compound of Formula (3) Preparation of aCompound of Formula (3) in which R¹⁰ is 2-Methylbenzothiazol-5-yl, Y isMethylene, and Z is Oxygen

A mixture of 2-methylbenzothiazol-5-ol (6.0 g, 36 mmol),(S)-(+)-epichlorohydrin (20 ml, 182 mmol), and potassium carbonate (20g, 144 mmol) in acetone (100 ml), was heated to reflux and allowed tostir overnight. The solution was allowed to cool and filtered throughCelite 512. The filtrate was evaporated under reduced pressure to yieldan oil, which was chromotgraphed on silica gel, eluting with 20% ethylacetate/hexanes, to yield2-methyl-5-(R)-(oxiran-2-ylmethoxy)benzothiazole as white solid.

EXAMPLE 2 Preparation of a Compound of Formula (5) A. Preparation of aCompound of Formula (5) in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ areHydrogen, Y is Methylene, Z is —O—, and R¹⁰ is 2-Methylbenzothiazol-5-yl

To 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole (2.21 g, 10 mmol), acompound of formula (3), was added tert-butyl 1-piperazinecarboxylate(1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). Theresulting solution was heated to 85° C. and stirred for 8 hours. Thesolvent was evaporated under reduced pressure, and the residue waschromatographed on silica gel, eluting with 5% methanol/methylenechloride, to yield tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylateas a clear oil.

B. Preparation of a Compound of Formula (5) in which R¹, R², R³, R⁵, R⁶,R⁷, R⁸ are Hydrogen, R⁴ is (S)-Methyl, Y is Methylene, Z is —O—, and R¹⁰is 2S-Methylbenzothiazol-5-yl

Similarly, following the procedure of Example 1A above, but replacingtert-butyl 1-piperazinecarboxylate with tert-butyl(3S)-3-methylpiperazinecarboxylate, the following compound of formula(5) was prepared, tert-butyl4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](3S)-3-methylpiperazinecarboxylate.

C. Preparation of a Compound of Formula (5a) in which R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸ are Hydrogen, Y is Methylene, Z is —O—, and R¹⁰ is 2Methoxyphenyl

A solution of 2-methoxy-1-(oxiran-2-ylmethoxy)benzene (0.989 g, 1.1mmol) and N-BOC-4-aminopiperidine (1 g, 5 mmol) in ethanol (10 ml) wasrefluxed for 2 hours. The solvent was then removed under reducedpressure, and the residue flash chromatographed, eluting with 0-5%methanol/dichloromethane, to provideN-{1-[(2R)-2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}(tert-butoxy)carboxamide,a compound of formula (5a).

D. Preparation of Compounds of Formula (5) and (5a), varying R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁰, Y, and Z

Similarly, following the procedure of Example 2A or 2C above, butoptionally replacing tert-butyl 1-piperazinecarboxylate with othercompounds of formula (4), or optionally replacingN-BOC-4-aminopiperidine with other compounds of formula (4a), andoptionally replacing 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole withother compounds of formula (3), or optionally replacing2-methoxy-1-(oxiran-2-ylmethoxy)benzene with other compounds of formula(3a), other compounds of formula (5) and (5a) are prepared.

EXAMPLE 3 Preparation of a Compound of Formula (6) A. Preparation of aCompound of Formula (6) in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ areHydrogen, Y is Methylene, Z is —O—, and R¹⁰ is 2-Methylbenzothiazol-5-yl

A solution of4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylicacid tert-butyl ester (2.9 g, 7.1 mmol), a compound of formula (5), wasdissolved in a 4N solution of HCl in dioxane (20 ml) and allowed to stirat room temperature for 4 hours. The solvent was evaporated underreduced pressure to yield a white solid. The white solid was dried underhigh vacuum, and then dissolved in methanol (250 ml). AG 1-X8 resin wasadded and the mixture shaken. Additional resin was added until a neutralpH was obtained. The resin beads were removed by filtration, andmethanol removed from the filtrate under reduced pressure, and theresidue placed under high vacuum overnight, to yield(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as anoil.

B. Preparation of a Compound of Formula (6) in which R¹, R², R³, R⁵, R⁶,R⁷, R⁸ are Hydrogen, R⁴ is (S)-Methyl, Y is Methylene, Z is —O—, and R¹⁰is 2-Methylbenzothiazol-5-yl

Similarly, following the procedure of Example 3A above, but replacing4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylicacid tert-butyl ester with tert-butyl(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinecarboxylate,the following compound of formula (6), (6′),was prepared,(2R)-1-((2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

C. Preparation of a Compound of Formula (6a) in which R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸ are Hydrogen, Y is Methylene, Z is —O—, and R¹⁰ is 2Methoxyphenyl

Similarly, following the procedure of Example 3A above, but replacing4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylicacid tert-butyl ester with(tert-butoxy)-N-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}carboxamide,the following compound of formula (6) was prepared,(2R)-1-(4-aminopiperidyl)-3-(2-methoxyphenoxy)propan-2-ol.

D. Preparation of a Compound of Formula (6), varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R¹⁰, Y, and Z

Similarly, following the procedure of Example 3A or 3C above, butreplacing 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole with othercompounds of formula (5) or (5a), other compounds of formula (6) or (6a)are prepared.

EXAMPLE 4 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Butylene, Y isMethylene, T and Z are —O—, R⁹ is Cyclopentyl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (7)

NaH (560 mg, 13.93 mmol, 60% disp. in mineral oil) was washed withhexanes (3×20 mL) in a pressure tube and toluene (6 mL,) was added. Thesolution was cooled to 0° C. and cyclopentanol (1 g, 11.61 mmol) intoluene (6 mL) was added over 20 min. After stirring at 0° C. for 30min., 1,4-dibromobutane (1.39 mL, 11.61 mmol) and KI (250 mg) wereadded. The solution was heated to 100° C. for 14 hours. Upon cooling,the reaction was quenched with NaCl (sat. aq.) and the product extractedwith EtOAc. The organic layer was dried over MgSO₄, filtered, andconcentrated. Purification of the residue via flash columnchromatography afforded (4-bromobutoxy)cyclopentane.

Step 2. Synthesis of the Formula I Compound

A solution of (4-bromobutoxy)cyclopentane (400 mg, 1.81 mmol) in EtOH (5mL) was treated with DIEA (0.64 mL, 3.62 mmol) and1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as preparedin Example 3A (557 mg, 1.81 mmol). The solution was stirred at reflux 15hours. Upon cooling, the product was concentrated and purified by flashcolumn chromatography (10% MeOH/EtOAc) to yield(2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 4A above, but optionallysubstituting (4-bromobutoxy)cyclopentane with other R⁹—O—X-Hal ethers,and optionally replacing1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with othercompounds of formula (6) or (6a), the following compounds of Formula Iwere prepared:

-   (2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohexyloxy]butyl}piperazinyl)propan-2-ol;-   (2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol;-   (2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;    and-   (2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

EXAMPLE 5 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Butylene, Y isMethylene, T and Z are —O—, R⁹ is Phenyl, and R¹⁰ is2-Methylbenzothiazol-5-yl

(4-Chlorobutoxy) benzene (320 mg, 1.39 mmol) in EtOH (17 Ml) was treatedwith DIEA (0.48 Ml, 2.78 mmol) and1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as preparedin Example 3A (427 mg, 1.39 mmol), then stirred 14 hours at 88° C. Uponcooling, concentrated in vacuo and purified on the Isco™ (10 g Redisep™columns, 100% EtOAc hold 2 min., 8 min. gradient to 20% MeOH/EtOAc, hold10 min) to provide(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 5A above, but optionallysubstituting (4-chlorobutoxy) benzene with other R⁹—O—X-Hal ethers, andoptionally replacing1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with othercompounds of formula (6) or (6a), the following compounds of Formula Iwere prepared:

-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]propan-2-ol;-   (2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;    and-   (2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

EXAMPLE 6 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Ethylene, Y isMethylene, T and Z are —O—, R⁹ is 2-Methylphenyl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (7)

2-Methyl-phenol (1 g, 9.25 mmol) in NaOH (aq) (3.24 mL, 12.96 mmol, 4Msoln.) was treated with dibromoethane (2.74 mL, 31.7 mmol) andt-butylammoniumhydrogen sulfate (catalytic), and then placed in aRobbins™ oven at 99° C. for 72 hours. The pH was then adjusted to ˜8with NaOH (4M aq. soln.) and the product extracted with CH₂Cl₂ (x3). Thecombined organic layer was washed with H₂O (x2) and brine, dried overMgSO₄. The resulting oil taken up in 4:1 hexane/EtOAc and passed througha plug of silica gel. The plug was then washed with 4:1 hexane/EtOAc andthe filtrate concentrated to provide crude2-bromo-1-(2-methylphenoxy)ethane.

Step 2. Synthesis of the Formula I Compound

To a solution of 2-bromo-1-(2-methylphenoxy)ethane (1.09 g, 5.09 mmol,crude) in EtOH (15 mL) was added(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol asprepared in Example 3A (250 mg, 0.81 mmol) and DIEA (1.5 mL, 8.6 mmol).The solution was stirred at reflux for 14 hours. Upon cooling, thesolution was concentrated to an oil and then purified on an Isco™ (100%EtOAc hold 2 min, 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) toafford(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl}propan-2-ol.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 6A above, but optionallyreplacing (2-bromo-1-(2-methylphenoxy)ethane with other R⁹—O—X-Halethers, and optionally replacing(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol withother compounds of formula (6) or (6a), the following compounds ofFormula I were prepared:

-   (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   (2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol;-   2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetic    acid;-   2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoic    acid; and-   3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoic    acid.

EXAMPLE 7 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Butylene, Y isMethylene, T and Z are —O—, R⁹ is Indane-5-yl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (7)

5-Indanol (1 g, 7.45 mmol) in NaOH_((aq)) (5.22 mL, 20.88 mmol, 4 Msoln.) was treated with dibromobutane (3.38 mL, 28.3 mmol) andt-butylammoniumhydrogensulfate (catalytic). The solution was placed in aRobbins™ oven for 14 hours at 99° C. Upon cooling, the pH was adjustedto ˜8 with 4 N NaOH. CH₂Cl₂ was then added and the solution washed withH₂O (×2) and brine. The organic layer was dried over MgSO₄ andconcentrated to an oil. The oil was then dissolved in 4:1 hexane/EtOAcand passed through a plug of silica gel which was then washed with 4:1hexane/EtOAc. The filtrate was concentrated to afford4-bromo-1-indan-5-yloxybutane.

Step 2. Synthesis of the Formula I Compound

A solution of 4-bromo-1-indan-5-yloxybutane (934 mg, 3.46 mmol, crude)in EtOH (10 mL) was treated with(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol asprepared in Example 3A (250 mg, 0.81 mmol) and DIEA (0.57 mL, 3.3 mmol)and refluxed for 14 hours. Upon cooling to RT, the solution was thenconcentrated under reduced pressure and purified via an Isco™ (100%EtOAc 4 min, 10 min gradient to 25% MeOH/EtOAc, hold 6 min.) to afford(2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 7A above, but optionallyreplacing 4-bromo-1-indan-5-yloxybutane ethane with other R⁹—O—X-Halethers, and optionally replacing1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with othercompounds of formula (6) or (6a), the following compounds of Formula Iwere prepared:

-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol;-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol;-   6-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]acetate;-   ethyl    3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoate;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetate;-   ethyl    2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoate;    and-   (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy]hexyl}piperazinyl)propan-2-ol.

EXAMPLE 8 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is a Covalent Bond, Yis Methylene, Z is —O—, T and R⁹ are Joined to form1-Phenyl-2-pyrrolidinone, and R¹⁰ is 2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (7)

1-Phenyl-2-pyrrolidinone (1 g, 6.2 mmol) in THF (60 mL, anhydrous) wascooled to −40° C. and LiHMDS (8 mL, 8 mmol, 1 M soln. in THF) was added.The resulting solution was stirred for 40 min. and tosyl chloride (1.78g, 9.33 mmol) was then added. After warming the solution to RT over a 14hour period, H₂O added to quench reaction. The solution was thenconcentrated to provide an oil. Next, the oil was redissovled in EtOAcand washed with H₂O and brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated to an oil once again. Purified via flashcolumn chromatography (4:1 hexane/EtOAc) provided3-chloro-1-phenylpyrrolidin-2-one.

Step 2. Synthesis of the Formula I Compound

To a solution of 3-chloro-1-phenylpyrrolidin-2-one (100 mg, 0.51 mmol)in EtOH (10 mL) was added1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as preparedin Example 3A (190 mg, 0.62 mmol) and Et₃N (0.2 mL, 1.43 mmol). Thesolution was stirred at 85° C. for 60 hours. Upon cooling, the solutionwas concentrated to an oil and purified via flash column chromatographyto afford3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylpyrrolidin-2-one.

EXAMPLE 9 A. Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is a Covalent Bond, Yis Methylene, Z is —O—, T and R⁹ are Joined to form1-(4-Chloropheny)1-2-pyrrolidinone-4-yl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (7)

a. Formation of R⁹/T Ring

4-Fluoroaniline (0.7 ml, 7.6 mmol) was added to 2-methylenebutanedioicacid (1.0 g, 7.6 mmol) in a sealed tube. The mixture was heated to 110degrees for 3 hours after which a precipitate formed. The reaction wasfiltered and the solid was dissolved in ethyl acetate and concetrated toyield 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (M+1=223.8).The product was taken to next step without determining mass.

b. Alkylation of the Carboxylic Acid

1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (unknown amount)was dissolved in 20 ml ethanol and cooled to 0° C. HCl gas was bubbledinto the solution until the solution became red in color. The reactionwas allowed to warm to room temperature and stir ovenight. The solventwas removed to yield ethyl1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (M+1=251.93).

c. Conversion of the Carboxylate to an Alcohol

To a solution of ethyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate(0.25 g, 1.0 mmol) in ethanol (10 ml) was added lithium chloride (0.085g, 2.0 mmol) and sodium borohydride (0.080 g, 2.0 mmol). The reactionwas stirred 24 hours at room temperature. The solvent was removed and 30ml water was added to the residue. The aqueous solution was acidifiedwith conc. HCl until the pH was ˜2-3. The acidic solution was extractedwas acidified with conc. HCl until the pH was ˜2-3. The acidic solutionwas extracted sodium sulfate and evaporated. The residue was purifiedusing preparative TLC (15:1 DCM:MeOH) to yield1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (H HNMR). This wasrepeated twice.

d. Addition of the Halide Leaving Group

To a cooled solution of1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (0.05 g, 0.25 mmol)in pyridine (3 ml) was added triphenylphosphine (0.130 g, 0.5 mmol). Thesolution was stirred and carbon tetrabromide (0.08 g, 0.25 mmol) wasadded in 3 separate portions. The reaction mixture was then allowed towarm to room temperature and stirred for three hours. The reaction wasquenched with methanol and the solvent removed. The residue wasdissolved in EtOAc (75 ml) and sequentially washed with ammoniumchloride (sat, 2×25 ml) and water (25 ml). The organic layer wasconcentrated and purified using preparative tlc (1:1 EtOac:Hexanes) toyield 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (HNMR).

Step 2. Synthesis of the Formula I Compound

A solution of 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (0.04g, 0.15 mmol),(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol 2×HCl(0.09 g, 0.24 mmol), and potassium carbonate (0.150 g, 1.15 mmol) inN,N′dimethylformamide (2 ml) was heated to 70° C. for 16 hours. Thesolution was filtered and the filtrate concentrated. The residue waspurified using preparative chromatography (15:1 DCM:MeOH) to yield4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one(M+1=498.99).

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 8A or 8B above, butoptionally replacing the formula (7) compound with other R⁹-T-X-Halcompounds, and optionally replacing1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with othercompounds of formula (6) or (6a), the following compounds of Formula Iwere prepared:

-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-methylphenyl)pyrrolidin-2-one;-   1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-vinylphenyl)azolidine-2,5-dione;-   3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylazolidine-2,5-dione;    and-   4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one.

EXAMPLE 10 Preparation of a Compound of Formula I in which R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Ethylene, Y isMethylene, T is —SO₂—NH—, Z is —O—, R⁹ is Indane-5-yl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1. Synthesis of a Compound of Formula (9)

To a solution of(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (500mg, 1.63 mmol) in EtOH (25 mL) was added N-(2-bromoethyl) phthalimide(435 mg, 1.71 mmol) and Et₃N (0.79 mL, 5.7 mmol). The reacting solutionwas shaken at 90° C. for 16 hours. Upon cooling, the solution wasconcentrated to an oil and purified via flash column chromatography (4:1EtOAc/MeOH) to afford2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azolidine-1,3-dione.

Step 2. Synthesis of a Compound of Formula (10)

A solution of2-(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azoline-1,3-dione(101 mg, 0.21 mmol) in MeOH (0.84 mL) was treated with hydrazine hydrate(0.07 mL) and stirred at RT for 14 hours. HCl (1 mL, conc) was added andthe solution was heated to 88° C. for 14 hours. Upon cooling, theresulting solid was filtered off and washed with H₂O and EtOAc. Thefiltrate was pH adjusted to >12 (NaOH) and extracted with EtOAc. Thecombined organic layers were then concentrated to afford(2R)-1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-olas an oil.

Step 3. Synthesis of the Formula I Compound

A solution of1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol(60 mg, 0.171 mmol) in DME (6 mL) was cooled to 0° C. and benzenesulfonyl chloride (0.022 mL, 0.172 mmol) was added. The solution wasstirred at 0° C. for 5 min and then at RT for 10 min. The reactionmixture was concentrated to an oil and purified via flash columnchromatography (9:1 CHCl₃/MeOH) to afford(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(phenylsulfonyl)amine.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 10A above, but optionallyreplacing benzene sulfonyl chloride with other R⁹SO₂-Hal compounds, andoptionally replacing(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol withother compounds of formula (6) or (6a), the following compounds ofFormula I were prepared:

-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-methylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-chlorophenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-trifluoromethoxy)phenylsulfonyl]amine;-   (3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butyl)[(4-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,5-dimethyl)phenylsulfonyl]amine;-   {[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   [(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(3-methylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine;-   (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(naphthylsulfonyl)amine;-   {[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;-   [(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;    and-   {[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine.

EXAMPLE 11 A. Preparation of a Compound of Formula I in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Ethylene, Y isMethylene, T is —NH—SO₂—, Z is —O—, R⁹ is Indane-5-yl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1—Preparation of a Compound of Formula (13)

Aniline (0.98 mL, 10.7 mmol) and Et₃N (1.8 mL, 12.9 mmol) in toluene (25mL) were treated with 2-chloro-1-ethanesulfonylchloride (1.1 mL, 10.5mmol). The exothermic reaction was stirred for 14 hours at roomtemperature. After stirring, the solution was diluted with EtOAc andwashed with HCl (˜10% aq. soln.). The organic layer concentrated andpurified via flash column chromatography (4:1 hexane/EtOAc) to affordtwo lots of phenyl(vinylsulfonyl)amine.

Step 2—Preparation of a Compound of Formula I

To a solution of phenyl(vinylsulfonyl)amine (141 mg, 0.77 mmol) and DIEA(0.47 mL, 4.9 mmol) in EtOH (7.5 mL) was added(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (470mg, 1.5 mmol, crude). The solution was heated for 2 hours at 85° C. on aJ-Kem™ block. Upon cooling, the reaction mixture was concentrated to anoil and purified via flash column chromatography (4:1 EtOAc/MeOH) toafford[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 11A above, but optionallyreplacing alanine and/or 2-chloro-1-ethanesulfonylchloride with othercompounds of formula (11) or (12), and/or optionally replacing1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with othercompounds of formula (6) or (6a), the following compounds of Formula Iwere prepared:

-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(methyl)phenyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine;-   [3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   (4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]naphthylamine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine;-   [(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl)sulfonyl][4-(tertbutyl)phenyl]amine;-   (2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   (3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine;    and-   [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine.

EXAMPLE 12 A. Preparation of a Compound of Formula I in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X and Y areMethylene, T is —NH—SO₂—, Z is —O—, R⁹ is Indane-5-yl, R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1—Preparation of Formula (7′)

A solution of 2-methylenesuccinic anhydride (500 mg, 4.46 mmol) andaniline (0.4 mL, 4.46 mmol) in CH₃Cl were shaken overnight. Aprecipitate formed, which was filtered off, washed with hexanes, anddried under vacuum to afford 2-[(N-phenylcarbamoyl)methyl]prop-2-enoicacid.

A suspension of the 2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid (700mg, 3.41 mmol) in Ac₂O (15 mL) was then treated with NaOAc (327 mg, 3.98mmol) and shaken for 14 hours at 89° C. The resulting clear solution wasdried on a Savant™, dissolved in EtOAc and washed with H₂O and brine.The organic layers were then dried down on Savant™ to yield3-methylene-1-phenylazolidine-2,5-dione, a compound of formula (7′).

Step 2—Preparation of a Compound of Formula I

A solution of 3-methylene-1-phenylazolidine-2,5-dione (250 mg, 1.33mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol(415 mg, 1.35 mmol) in AcOH (10 mL, glacial) was stirred 14 hours at 50°C. Concentrated in the Savant™ and residue taken up in EtOAc and washedwith NaHCO₃ (sat. aq. soln.), H₂O and brine, dried over MgSO₄, filteredand concentrated. Purification via flash column chromatography (gradient5 to 10% MeOH/EtOAc) afforded3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-phenylazolidine-2,5-dione.

B. Preparation of Other Compounds of Formula I

Similarly, following the procedure of Example 12A above, but optionallyreplacing 3-methylene-1-phenylazolidine-2,5-dione with other compoundsof formula (7′) and/or optionally replacing(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol withother compounds of formula (6) or (6a), the following compounds ofFormula I were prepared:

-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-phenylazolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-naphthylazolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;-   1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;-   1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;    and-   1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione.

EXAMPLE 13 A. Preparation of a Compound of Formula I in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —N<, X is Ethylene, Y isMethylene, T is —C(O)NH—, Z is —O—, R⁹ is Indane-5-yl, and R¹⁰ is2-Methylbenzothiazol-5-yl

Step 1—Preparation of Formula (7)

To a cooled (0° C.) solution of 2-bromoethylamine HBr salt (4.7 g, 23mmol) in diethyl ether (35 ml) and saturated sodium bicarbonate (50 ml)was added dropwise a solution of 4-(trifluoromethyl)benzoyl chloride(5.0 g, 24 mmol) in diethyl ether (15 ml) over one hour. The reactionwas stirred vigorously and allowed to warm to room temperature and thenstirred at room temperature for 48 hours. The ether layer was separatedand concentrated. The product,N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=295.9) wastaken to the next step without further purification.

Step 2—Preparation of Formula (7a′)

A mixture of N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.6g, 2 mmol), BOC-piperazine (0.38 g, 2 mmol), and potassium carbonate(0.56 g, 4 mmol) in acetone was heated to reflux for 2 hours. Thereaction was then cooled and concentrated. The product was isolatedusing column chromatography (EtOAc:Hexanes 1:1) to yield tert-butyl4-(2-{[4-(trifluoromethyl)phenyl]carbonylamino}ethyl)piperazinecarboxylate(M+1=402.1)

Step 3—Preparation of Formula (7a)

4-(2-{[4-(trifluoromethyl)phenyl]carbonylamino}ethyl)piperazinecarboxylate (0.2 g, 0.5 mmol) was dissolved in trifluoroacetic acid(TFA) (10 ml). The solution was allowed to stir at room temperature for24 hours. The acid was removed under vacuum and the product,N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide was takento the next step as a TFA salt.

Step 4—Preparation of Formula (I)

To a solution ofN-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2 g,0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml, 1.5mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (0.09 g,0.42 mmol). The reaction was heated to 85 degrees for four hours. Themixture was then concentrated in vacuo and purified using preparativethin layer chromatography (10:1 DCM:MeOH) to yieldN-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-(trifluoromethyl)phenyl]carboxamide(M+1=523.0).

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 13A above, but optionallyreplacing N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide withother compounds of formula (7), and/or optionally replacing5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole with other compoundsof formula (3), the following compounds of Formula I were prepared:

-   (2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide;-   N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzamide;-   (4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide;    and-   (4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide.

EXAMPLE 14 Preparation of a Compound of Formula (5b) in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Y is Methylene, Z is —O—, andR¹⁰ is 2-Methylbenzothiazol-5-yl

To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (2.0g, 9.25 mmol) and piperidin-4-one, chloride (1.25 g, 9.25 mmol) inethanol was added diisopropylethylamine (1.6 ml, 9.0 mmol). The mixturewas heated to reflux for 16 hours. The solvent was removed and theresidue purified by column chromatography (10:1 DCM:MeOH) followed bypreparative TLC (10:1 DCM:MeOH) to yield1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one.

EXAMPLE 15 A. Preparation of a Compound of Formula (7b) in which R⁹ andT are Joined to form (3R)-3-Amino-1-(4-Chlorophenyl)Pyrrolidin-2-one

Step 1—Addition of Protected Methionine Group to Substituted Amine

CBZ-d-Methionine (5.4 g, 20 mmol), N-hydroxybenzotriazole H₂O (HOBt, 3.0g, 20 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HBTU, 7.7 g, 20 mmol), 4-(dimethylamino)-pyridine(DMAP, ˜0.020 g, ˜0.16 mmol) and triethylamine (2.8 ml, 20 mmol) wereadded to a solution of 4-chloroaniline (1.3 g, 10 mmol) in THF. Thenon-homogeneous solution was stirred at room temperature for 24 hours.The solvent was then removed and the residue taken into ethyl acetate(˜200 ml) and washed sequentially with NaHCO₃ (3×100 ml), 10% citricacid (3×100 ml), water (3×100 ml) and saturated NaCl (1×75 ml). Theorganic layer was then dried with sodium sulfate, filtered, andconcentrated to yield(2R)—N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]butanamide(M+1=393.26)

Step 2—Alkylation of Methionine Substituent

To neat(2R)-N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]butanamide(2.0 g, 5.09 mmol) was added methyl iodide (10 ml, 161 mmol). Thesolution was allowed to stir for 48 hours. Methyl iodide was thenremoved under vacuum to yield(2R)-N-(4-chlorophenyl)-5-methyl-2-[(phenylmethoxy)carbonylamino]-5-thiahexanamide,iodide.

Step 3—Ring Closure to Prepare R⁹/X 2-Oxypyrrolidine Structure

To a cooled (0°) solution of(2R)—N-(4-chlorophenyl)-5-methyl-2-[(phenylmethoxy)carbonylamino]-5-thiahexanamide,iodide (0.53 g, 1.0 mmol) in DMF (5.0 ml) and THF (5.0 ml) was added NaH(60% suspension in oil, 0.06 g, 1.5 mmol). The reaction mixture waswarmed to room temperature and then stirred until the desired productwas seen using thin layer chromamtography (EtOAc). The solvent wasremoved and the product then purified using preparative chromatography(pure EtOAc) to yieldN-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamide(M+1=366.93)

Step 4—Deprotection of the (7b) Compound

To a solution ofN-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamide(0.2 g, 0.58 mmol) in ethanol (10 ml) and cyclohexene (4 ml) was addedpalladium hydroxide (40 mg). The reaction was refluxed vigorouslyovernight. Palladium was removed by filtration and the filtrate wasconcentrated to yield (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one.

EXAMPLE 16 A. Preparation of a Compound of Formula I in which R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, Q is —NH—CH<, X is a CovalentBond, Y is Methylene, -, Z is —O—, R⁹ and T are Joined to form(3R)-3-Amino-1-(4-Chlorophenyl)Pyrrolidin-2-one, and R¹⁰ is2-Methylbenzothiazol-5-yl

To a solution of (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one asprepared in Example 14 (0.08 g) in EtOH (3 ml) was added1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-oneas prepared in Example 13 (0.15 g, 0.53 mmol) and sodiumtriacetoxyborohydride (0.112 g, 0.53 mmol). The reaction was stirred atroom temperature for 48 hours. The solvent was removed and the residuepurified using preparative TLC (10:1 DCM:MeOH) to yield(3R)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)-1-(4-chlorophenyl)pyrrolidin-2-one.

B. Preparation of other Compounds of Formula I

Similarly, following the procedure of Example 16A above, but optionallyreplacing (3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one with othercompounds of formula (7b), and/or optionally1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-onewith other compounds of formula (5b), the following compounds of FormulaI were prepared:

-   (3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   (3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-chlorophenyl)pyrrolidin-2-one;-   (3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one;-   3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(2-fluorophenyl)pyrrolidin-2-one;-   3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;-   (3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}pyrrolidin-2-one;    and-   4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one.

EXAMPLE 17

Several compounds of Formula I prepared as shown in the above procedureswere characterized by NMR and mass spectrometry. For example:

(4-Trifluoromethylphenyl)-N-(2-{4-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-yloxy)Propyl]Piperazinyl}Ethyl)Carboxamide

¹H NMR (CDCl₃) δ 7.9 (2H,d), 7.7 (2H, d), 7.45 (1H, d), 7.05 (1H,dd),6.95 (1H,m), 4.18 (1H, m), 4.05 (2H, m), 3.6 (2H, m), 2.8 (3H,s),2.8-2.5 (12H, m)

(3R)-1-(4-Fluorophenyl)-3-({1-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-yloxy)Propyl](4-Piperidyl)}Amino)Pyrrolidin-2-one

¹H NMR (CDCl₃) δ 7.65 (1H,d), 7.6 (2H, m), 7.42 (1H,d), 7.05 (3H,m),4.15 (1H,m), 4.05 (2H,d), 3.75 (2H,m), 3.65 (1H, t), 3.05 (1H,m), 2.88(1H,m), 2.8 (3H,s) 2.7 (1H,m), 2.4-2.6 (4H,m), 2.18 (1H,m), 1.98 (3H,m),1.5 (2H,m)

(3R)-3-({1-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-Yloxy)Propyl](4-Piperidyl)}Amino)-1-[4-(Trifluoromethyl)Phenyl]Pyrrolidin-2-one

¹H NMR (CDCl₃) δ 7.8 (2H, d), 7.62 (3H, m), 7.4 (1H, s), 7.0 (1H,dd),4.4 (1H,m), 4.1 (1H, m), 4.0 (1H, m), 3.8 (2H, m), 3.65 (1H, t),3.4-3.25 (2H, m), 2.97 (3H,m), 2.8 (3H, s), 2.9-2.7 (2H, m), 2.55 (1H,m), 2.1 (2H,m), 2.0 (1H, m), 1.75 (2H,m)

4-({14-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-yloxy)Propyl]Piperazinyl}Methyl)-1-(4-Fluorophenyl)Pyrrolidin-2-one

¹H NMR (CDCl₃) δ 7.65 (1H, d), 7.6 (2H,m), 7.45 (1H,s), 7.05 (3H,m),4.18 (1H,m), 4.05 (2H,m), 3.95 (1H,t), 3.6 (1H,m), 2.8 (3H, s), 2.7-2.4(15, mm)

The following examples illustrate the preparation of representativepharmaceutical formulations containing a compound of Formula I, such asthose prepared in accordance with Examples 1-16 above.

EXAMPLE 18

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 19

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

EXAMPLE 20

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

EXAMPLE 21

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

i. Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as10% solution in sterile water) Sodium carboxymethyl starch 4.5 mgMagnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 22

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 23

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose, and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

EXAMPLE 24

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 25

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP  50 mg/mlGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF q.s.

EXAMPLE 26

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

EXAMPLE 25

Sustained Release Composition Weight Preferred Most Preferred IngredientRange (%) Range (%) Range (%) Active ingredient 50-95 70-90 75Microcrystalline cellulose (filler)  1-35  5-15 10.6 Methacrylic acidcopolymer  1-35   5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate 0.5-5.01-3 2.0

The sustained release formulations of this invention are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed(dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

EXAMPLE 28

Mitochondrial Assays

Rat heart mitochondria are isolated by the method of Nedergard andCannon (Methods in Enzymol. 55, 3, 1979).

Palmitoyl CoA oxidation—The Palmityl CoA oxidation is carried out in atotal volume of 100 micro liters containing the following agents: 110 mMKCl, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl₂, 0.1 mM EDTA, 14.7microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52micrograms of mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA(Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters perassay). The compounds of this invention are added in a DMSO solution atthe following concentrations: 100 micro molar, 30 micro molar, and 3micro molar. In each assay, a DMSO control is used. After 15 min at 30°C., the enzymatic reaction is centrifuged (20,000 g for 1 min), and 70microliters of the supernatant is added to an activated reverse phasesilicic acid column (approximately 0.5 ml of silicic acid). The columnis eluted with 2 ml of water, and 0.5 ml of the eluent is used forscintillation counting to determine the amount of C¹⁴ trapped as C¹⁴bicarbonate ion.

The compounds of the invention show activity as fatty acid oxidationinhibitors in this assay.

EXAMPLE 29

Perfusate

Langendorff perfusion is conducted using a Krebs-Henseleit solutioncontaining: (mM) NaCl (118.0), KCl (4.7), KH₂PO₄ (1.2), MgSO₄ (1.2),CaCl₂ (2.5), NaHCO₃ (25.0) and glucose (5.5 or 11) (Finegan et al.1996). The working heart perfusate consists of a Krebs-Henseleitsolution with the addition of palmitate (0.4 or 1.2 mM) pre-bound to 3%bovine serum albumin (essentially fatty acid free BSA) and insulin (100μU/ml). Palmitate is initially dissolved in an ethanol:water mixture(40%:60%) containing 0.5-0.6 g Na₂CO₃ per g of palmitate. Followingheating to evaporate the ethanol, this mixture is then added to the 3%BSA-Krebs-Henseleit mixture (without glucose) and allowed to dialyze(8000 MW cut-off) overnight in 10 volumes of glucose-freeKrebs-Henseleit solution. The next day, glucose is added to the solutionand the mixture is filtered through glass microfiber filters (GF/C,Whatman, Maidstone, England) and kept on ice, or refrigerated, prior touse. The perfusate is continuously oxygenated with a 95% CO₂, 5% O₂ gasmixture while in the perfusion apparatus to main aerobic conditions.

Heart Perfusion Protocols

Rats are anesthetized with pentobarbital (60 mg/kg, intraperitoneally)and hearts are rapidly removed and placed in ice-cold Krebs-Henseleitsolution. The hearts are then rapidly cannulated via the aortic stumpand Langendorff perfusion at constant pressure (60 mm Hg) is initiatedand continued for a 10-min equilibration period. During thisequilibration period, the pulmonary artery is cut, and excess fat andlung tissue removed to reveal the pulmonary vein. The left atrium iscannulated and connected to the preload line originating from theoxygenation chamber. After the 10-min equilibration period, hearts areswitched to working mode (by clamping off the Langendorff line andopening the preload and afterload lines) and perfused at 37° C. underaerobic conditions at a constant left atrial preload (11.5 mm Hg) andaortic afterload (80 mm Hg). The compliance chamber is filled with airadequate to maintain developed pressure at 50-60 mm Hg. Perfusate isdelivered to the oxygenation chamber via a peristaltic pump from thereservoir chamber that collected aortic and coronary flows as well asoverflow from the oxygenator.

Typically, hearts are perfused under aerobic conditions for 60 minutes.Hearts are paced at 300 beats/min throughout each phase of the perfusionprotocol (voltage adjusted as necessary) with the exception of theinitial 5 min of reperfusion when hearts are allowed to beatspontaneously.

At the end of the perfusion protocol, hearts are rapidly frozen usingWollenberger clamps cooled to the temperature of liquid nitrogen. Frozentissues are pulverized and the resulting powders stored at −80° C.

Myocardial Mechanical Function

Aortic systolic and diastolic pressures are measured using a Sensonor(Horten Norway) pressure transducer attached to the aortic outflow lineand connected to an AD Instruments data acquisition system. Cardiacoutput, aortic flow and coronary flow (cardiac output minus aortic flow)are measured (ml/min) using in-line ultrasonic flow probes connected toa Transonic T206 ultrasonic flow meter. Left ventricular minute work (LVwork), calculated as cardiac output x left ventricular developedpressure (aortic systolic pressure—preload pressure), is used as acontinuous index of mechanical function. Hearts are excluded if LV workdecreased more than 20% during the 60-min period of aerobic perfusion.

Myocardial Oxygen Consumption and Cardiac Efficiency

Measuring the atrial-venous difference in oxygen content of theperfusate and multiplying by the cardiac output provides an index ofoxygen consumption. Atrial oxygen content (mmHg) is measured inperfusate in the preload line or just prior to entering the left atria.Venous oxygen content is measured from perfusate exiting the pulmonaryartery and passing through in-line O₂ probes and meters MicroelectrodesInc., Bedford, N.H. Cardiac efficiency is calculated as the cardiac workper oxygen consumption.

Measurement of Glucose and Fatty Acid Metabolism

Determining the rate of production of ³H₂O and ¹⁴CO₂ from[³H/¹⁴C]glucose in the isolated working rat model allows a direct andcontinuous measure of the rates of glycolysis and glucose oxidation.Alternatively, the measure of the production of ³H₂O from[5-³H]palmitate provides a direct and continuous measure of the rate ofpalmitate oxidation. Dual labelled substrates allows for thesimultaneous measure of either glycolysis and glucose oxidation or fattyacid oxidation and glucose oxidation. A 3-ml sample of perfusate istaken from the injection port of the recirculating perfusion apparatusat various time-points throughout the protocol for analysis of ³H₂O and¹⁴CO₂ and immediately placed under mineral oil until assayed formetabolic product accumulation. Perfusate is supplemented with[³H/¹⁴C]glucose or [5-³H]palmitate to approximate a specific activity of20 dpm/mmol. Average rates of glycolysis and glucose oxidation arecalculated from linear cumulative time-courses of product accumulationbetween 15 and 60 minutes for aerobic perfusion. Rates of glycolysis andglucose oxidation are expressed as μmol glucose metabolized/min/g drywt.

Measurement of Myocardial Glycolysis

Rates of glycolysis are measured directly as previously described(Saddik & Lopaschuk, 1991) from the quantitative determination of ³H₂Oliberated from radiolabeled [5-³H]glucose at the enolase step ofglycolysis. Perfusate samples are collected at various time-pointsthroughout the perfusion protocol. ³H₂O is separated from the perfusateby passing perfusate samples through columns containing Dowex 1-X 4anion exchange resin (200-400 mesh). A 90 g/L Dowex in 0.4 M potassiumtetraborate mixture is stirred overnight, after which 2 ml of thesuspension is loaded into separation columns and washed extensively withdH₂O to remove the tetraborate. The columns are found to exclude98-99.6% of the total [³H]glucose (Saddik & Lopaschuk, 1996). Perfusatesamples (100 μl) are loaded onto the columns and washed with 1.0 mldH₂O. Effluent is collected into 5 ml of Ecolite Scintillation Fluid(ICN, Radiochemicals, Irvine, Calif.) and counted for 5 min in a BeckmanLS 6500 Scintillation Counter with an automatic dual (³H/¹⁴C) quenchcorrection program. Average rates of glycolysis for each phase ofperfusion are expressed as μmol glucose metabolized/min/g dry wt asdescribed above.

Measurement of Myocardial Glucose Oxidation

Glucose oxidation is also determined directly as previously described(Saddik & Lopaschuk, 1991) by measuring ¹⁴CO₂ from [¹⁴C]glucoseliberated at the level of pyruvate dehydrogenase and in the Krebs cycle.Both ¹⁴CO₂ gas exiting the oxygenation chamber and [¹⁴C]bicarbonateretained in solution are measured. Perfusate samples are collected atvarious time-points throughout the perfusion protocol. ¹⁴CO₂ gas iscollected by passing the gas exiting the oxygenator through a hyaminehydroxide trap (20-50 ml depending on perfusion duration). Perfusatesamples (2×1 ml), which were stored under oil to prevent the escape ofgas by equilibration with atmospheric CO₂, are injected into 16×150 mmtest tubes containing 1 ml of 9 N H₂SO₄. This process releases ¹⁴CO₂from the perfusate present as H¹⁴CO₃ ⁻. These duplicate tubes are sealedwith a rubber stopper attached to a 7-ml scintillation vial containing a2×5 cm piece of filter paper saturated with 250 μl of hyamine hydroxide.The scintillation vials with filter papers are then removed and EcoliteScintillation Fluid (7 ml) added. Samples are counted by standardprocedures as described above. Average rates of glucose oxidation foreach phase of perfusion are expressed as μmol glucose metabolized/min/gdry wt as described above.

Measurement of Myocardial Fatty Acid Oxidation

Rates of palmitate oxidation are measured directly as previouslydescribed (Saddik & Lopaschuk, 1991) from the quantitative determinationof ³H₂O liberated from radiolabeled [5-³H]palmitate. H₂O is separatedfrom [5-³H]palmitate following a chloroform:methanol (1.88 ml of 1:2v/v) extraction of a 0.5 ml sample of buffer then adding 0.625 ml ofchloroform and 0.625 ml of a 2M KCL:HCl solution. The aqueous phase isremoved and treated with a mixture of chloroform, methanol and KCl:HCl(1:1:0.9 v/v). Duplicate samples are taken from the aqueous phase forliquid scintillation counting and rates of oxidation are determinedtaking into account a dilution factor. This results in >99% extractionand separation of ³H₂O from [5-³H]palmitate. Average rates of glucoseoxidation for each phase of perfusion are expressed as μmol glucosemetabolized/min/g dry wt as described above.

Dry to Wet Ratios

Frozen ventricles are pulverized at the temperature of liquid nitrogenwith a mortar and pestle. Dry to wet determinations are made by weighinga small amount of frozen heart tissue and re-weighing that same tissueafter 24-48 hr of air drying and taking the ratio of the two weights.From this ratio, total dry tissue can be calculated. This ratio is usedto normalize, on a per g dry weight basis, rates of glycolysis, glucoseoxidation and glycogen turnover as well as metabolite contents.

The compounds of the invention showed activity as fatty acid oxidationinhibitors in the above assays.

REFERENCES

-   1. Finegan B A, Gandhi M, Lopaschuk G D, Clanachan A S, 1996.    Antecedent ischemia reverses effects of adenosine on glycolysis and    mechanical function of working hearts. American Journal of    Physiology 271: H2116-25.-   2. Saddik M, Lopaschuk G. D., 1991. Myocardial triglyceride turnover    and contribution to energy substrate utilization in isolated working    rat hearts. Journal of Biological Chemistry 266: 8162-8170.

All patents and publication cited above are hereby incorporated byreference.

1. A compound of Formula I:

wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen; R⁹ isheteroaryl selected from the group consisting of five and six memberedmonocyclic having one or two heteroatoms selected from N and Ooptionally substituted with 1 to 3 substituents selected from alkyl andhalogen substituted alkyl, and nine to twelve membered bicyclicheterocycles having one or two heteroatoms selected from N and Ooptionally substituted with 1 to 3 substituents selected from alkyl,halogen substituted alkyl, and oxo; R¹⁰ is benzothiazol-5-yl optionallysubstituted with alkyl; T is —O—; Q is —N>; X is an optionallysubstituted alkylene of 1-6 carbon atoms; Y is optionally substitutedalkylene of 1-3 carbon atoms; and Z is —O—.
 2. The compound of claim 1,wherein R¹⁰ is benzothiazol-5-yl substituted with methyl.
 3. Thecompound of claim 2, wherein R⁹ is a five or six membered monocyclicheteroaryl having one or two heteroatoms selected from N and Ooptionally substituted with 1 to 3 substituents selected from alkyl andhalogen substituted alkyl.
 4. The compound of claim 3, namely(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol.5. The compound of claim 2, wherein R⁹ is a nine to twelve memberedbicyclic heterocycle having one or two heteroatoms selected from N and Ooptionally substituted with 1 to 3 substituents selected from alkyl,halogen substituted alkyl, and oxo.
 6. The compound of claim 5, namely6-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one.7. A method of treating a disease state chosen from diabetes, damage toskeletal muscles resulting from trauma or shock and a cardiovasculardisease, selected from atrial arrhythmia, intermittent claudication,ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina,unstable angina, congestive heart failure, and myocardial infarcation ina mammal by administration of a therapeutically effective dose of acompound of claim
 1. 8. The method of claim 7, wherein the disease is acardiovascular disease selected from atrial arrhythmia, intermittentclaudication, ventricular arrhythmia, Prinzmetal's (variant) angina,stable angina, unstable angina, congestive heart failure, and myocardialinfarction.
 9. The method of claim 7, wherein the disease state isdiabetes.
 10. The method of claim 8, wherein the disease state iscongestive heart failure.
 11. A pharmaceutical composition comprising atleast one pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of claim 1.